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Three decades after its introduction, pharmacokinetic population approaches have become a reference method for drug modelling, particularly in paediatrics. The main practical limitation in this specific population is the collected blood volume. Pharmacokinetic population approaches using sparse sampling may resolve this issue. The pharmacokinetics of many drugs have been studied during the last 25 years using such methods. This review summarizes all of the published studies concerning population pharmacokinetic approaches in paediatric subjects from neonate to 2 years old. A literature search was conducted using the PubMed database, from 1985 to December 2010, using the following terms: pharmacokinetic(s), population, paediatric/pediatric and neonate(s). Articles were excluded if they were not pertinent according to our criteria. References of all relevant articles were also evaluated. Ninety-eight studies were included in this review. The following information was extracted from the articles: drug name, therapeutic class, population size, age of patients, number of samples per patient, covariates used for clearance and volume of distribution estimates, software used for modelling and validation methods. An increasing rate of publications over the years was observed; 44 different drugs were studied using a pharmacokinetic population approach. Antibacterials were the most studied class of drugs, including a large number of studies devoted to vancomycin and gentamicin. It must be underlined that few studies have been performed on anticonvulsant drugs and anaesthetics used in clinical daily practice conditions.

Population pharmacokinetic (PK) (or pharmacodynamic (PD)) modelling aims to analyse the variability of drug kinetics (or dynamics) between numerous subjects belonging to a population. Such variability includes inter- and intra-individual sources leading to important differences between the variation ranges, the relative concentrations and the global shapes of PK profiles. These various sources of variability suggest that the distance metrics between the subjects can be examined under different aspects. Some subjects are so distant from the majority that they tend to be atypical or outliers. This paper presents three multivariate statistical methods to diagnose the outliers within a full population PK dataset, prior to any modelling step. Each method combined all the concentration-time variables to analyse the differences between patients by referring to a distance criterion: (a) Correspondence analysis (CA) used the chi-square distance to highlight the most atypical profiles in terms of relative concentrations; (b) Mahalanobis distance was calculated to extract PK profiles showing atypical shapes due to atypical variations in concentration; (c) Andrews method combined all the concentration variables into a Fourier transformation to give sine-cosine curves showing the clustering behaviours of subjects under the Euclidean distance criterion. After identification of outlier subjects, these methods can also be used to extract the concentration values which cause the atypical states of the patients. Therefore, the outliers will incorporate different variability sources of the PK dataset according to each method and independently of any PK modelling. Finally, a significant positive trend was found between the number of times outlier concentrations were detected (by one, two or three diagnostics) and the NPDE metrics of these concentrations (after a PK modelling): NPDE were highest when the corresponding concentration was detected by more diagnostics a priori. The application of a priori outlier diagnostics is illustrated here on two PK datasets: stimulated cortisol by synacthen and capecitabine administrated orally.

Biological rhythms may influence drug response (chronopharmacology) and some chronopharmacological studies have underlined the influence of time of day on drug pharmacodynamics and pharmacokinetics. The aim of the present review is to underline how biological rhythms may interfere with drug kinetics and to try to underline when, how, and why taking into account the moment of administration of a drug. Many physiological factors, possibly implicated in different steps of the fate of drugs in the organism (e.g., absorption, distribution, metabolism, and elimination) vary along the 24 h scale. Taking into account biological rhythms in kinetic studies, should be indicated when the concerned drug will be used in a chronobiological disease (e.g., asthma, cancer, depression, hypertension, gastrointestinal diseases, rheumatisms), etc. In case of a drug characterised by a high inter- and intra-variability, a narrow therapeutic range or when the drug will be further used following a once-a-day formulation. It is of importance to rigorously control factors which are known to influence pharmacokinetic processes in chronokinetic studies. Time of day has to be regarded as an additional variable to influence the kinetics of a drug., ((Copyright) 2008 Wiley-Liss, Inc.)

Pharmacokinetic studies can be performed before or after a drug is marketed. Indeed, extensive use of a new drug can uncover situations that it has not been possible to investigate before market application. Hospital departments of pharmacology are often involved in these complementary studies. They can design the study, initiate it in a clinical investigation centre, measure plasma concentrations, analyse the pharmacokinetic data, and write the report. If the extent of the scientific involvement of public pharmacology laboratories is strictly demarcated, financial support for nonsponsored studies by the pharmaceutical industry is problematical. Indeed, it is difficult to obtain funds to study the concentration-toxicity relationship or a drug-drug interaction for a compound for which the patent has expired. In addition, such studies have an excess cost, mainly because of the expense associated with drug measurements. Also, the medical time devoted to research is not rewarded by institutions. This situation will become more complicated because of the restrictive legislative framework imposed by the European directive.

Absorption, distribution, metabolism and elimination are influenced by many different physiological functions of the body which may vary with time of day. Thus, the pharmacokinetic parameters characterising these different steps, conventionally considered to be constant in time, depend on the moment of drug administration. Time of day has to be regarded as an additional variable influencing the kinetics of a drug. Chronokinetic studies have been reported for many drugs in an attempt to explain chronopharmacodynamic phenomena and demonstrate that the time of administration is a possible factor of variation in the kinetics of a drug. In this paper this is illustrated with the chronopharmacokinetics of cardiovascular and nonsteroidal anti-inflammatory drugs. Time-dependent changes in kinetics may proceed from circadian variations at each step, e.g. absorption, distribution, metabolism and elimination. Thus, circadian variations in gastric acid secretion and pH, motility, gastric emptying time, gastrointestinal blood flow, drug protein binding, liver enzyme activity and/or hepatic blood flow, glomerular filtration, renal blood flow, urinary pH and tubular resorption may play a role in such kinetic variations. New tools, such as new formulation procedures or pumps with constant or programmable delivery rates, now make it possible to deliver a drug at a definite time, or during a definite span of time and at a controlled rate in chronokinetic studies. Microdialysis would be of particular interest in chronopharmacological and chronokinetics studies, but, surprisingly, very few chronobiological studies have been conducted using this technique. With regard to new models and concepts in chronokinetics, pharmacokinetic-pharmacodynamic modelling may be useful, and modelling of the chronopharmacological patterns of drug response and kinetics have been attempted by some authors. Drug chronopharmacokinetic knowledge may be clinically relevant as it may have implications for drug prescription by modulating the distribution of the total daily dose along the 24-hour scale. However, it seems reasonable to consider chronopharmacokinetic studies in specific cases related to patients, illness or the drug itself. When conducting a chronokinetic study it is not only necessary to take into account differences in the time of administration but to also have strict control of all other possible variables which are known to influence pharmacokinetic processes.

Chronopharmacokinetics deals with the study of the temporal changes in absorption, distribution, metabolism and elimination and thus takes into account the influence of time of administration on these different steps. In the last decade, numerous studies have been devoted to chronokinetics: recent advances will be reviewed in the first part. As representative examples, the main chronokinetic changes of anaesthetics, cardiovascular active drugs and antiinflammatory drugs in men are listed. Temporal changes can be involved at each step of the sequence of pharmacokinetic processes: temporal variations in drug absorption from the gastro-intestinal tract, in plasma protein binding and drug distribution, in drug metabolism (temporal variations in enzyme activity, hepatic blood flow) and in renal drug excretion may play a role. Thus, the time of administration of a drug is an important source of variation which must be taken into account in kinetic studies and particular methodological aspects of chronokinetics are needed. In a chronopharmacokinetic study many factors of variation must be controlled: factors related to the drug itself (influence of food, galenic formulation, drug interactions), subject related-factors (age, gender, pathology, posture, exercise, synchronization) and factors related to the conditions of the administration (single or repeated dosing, constant rate delivery, route of administration). In conclusion, there are some instances in which a chronokinetic study is needed: 1) when possible daily variations in pharmacokinetics may be responsible for time dependent variations in drug effects, 2) when drugs have a narrow therapeutic range, 3) when symptoms of a disease are clearly circadian phase-dependent (e.g. nocturnal asthma, angina pectoris, myocardial infarction, ulcer disease) 4) when drug plasma concentrations are well correlated to the therapeutic effect in case the latter is circadian phase-dependent. Variables influencing pharmacokinetics such as fasting, meals and meal times, galenic formulation, posture, activity-rest, have to be controlled according to the aim of the investigation. The main aim of chronokinetic studies is to control the time of administration which among others, can be responsible for variations of drug kinetics but also may explain chronopharmacological effects observed with certain drugs.

The pharmacokinetic parameters of drugs vary largely and predictably as a function of their dosing time along the 24-hr scale (and also the year and the menstrual cycle) in Man. Such chronopharmacokinetics have been described following single or repeated doses via the oral or the venous route, and whether drug halflife is short or long. Moreover continuous infusion of a drug at a constant rate cannot maintain constant plasma levels. Such phenomena are accounted for by circadian (and other) rhythms which characterize absorption, protein binding, transmembrane flux, as well as liver and kidney metabolism and biliary and urinary excretions. It is anticipated that the knowledge of the physical and chemical properties of a drug and that of the circadian organization of the main physiologic functions involved into its bioavailability will allow to predict its chronopharmacokinetics.